Discovery of a new chemical reaction, a fundamental property of nature, is a major finding. For example, without the discovery of the Haber process, which resulted in nitrogen fixation, modern fertilizers could not be manufactured, and the current world population growth would not be sustainable.
In 2011, at Duke University and the Durham Va. Medical Center, we discovered that a stereocomplex chemical reaction occurred between L-lactate and Polymer D-lactic acid (PDLA). (Goldberg, Weinberg 2014, 2016) A stereocomplex is a new substance that is formed when a molecule and its mirror image (D and L or enantiomers) come together with the proper orientation. The reaction occurs spontaneously and rapidly without a catalyst or enzyme. Later we discovered that D-lactic acid dimer (two D-lactic acids connected by an ester bond), synthesized at the Duke Small Molecule Synthesis Facility, would “sequester or trap” L-lactate.
L-lactate has many potential functions. It can act as a neurotransmitter, a buffer for the efflux of hydrogen ions in some cancer cells, and an intermediary in glycolysis. Otto Warburg, a preeminent biochemist of the 20th century who was nominated for 51 Nobel Prizes, discovered that most cancer cells utilize the glycolytic pathway to produce ATP (the “Warburg effect”). This discovery led to the common use of positron emission tomomgraphy (PET) scans for imaging cancer in vivo.
In normal cells, most glucose is metabolized by three separate but linked pathways (glycolysis, the Krebs cycle, and oxidative phosphorylation) to produce ATP. Final products of glycolysis include hydrogen ions that are effluxed from the cell. These hydrogen ions must be buffered to maintain electrical neutrality in the cell, and one of those buffering ions is often L-lactate. In a normal cell, the hydrogen ion produced from glycolysis is primarily passaged to oxidative phosphorylation, but many cancer cells do not have that option. Therefore, it would seem that sequestering L-lactate would have significant biologic effects on those cancer cells which depend upon glycolysis for generation of ATP.
We believe that D-lactic acid dimer would be unlikely to produce effects as a systemically administered drug, because the concentration required to form the stereocomplex is not realistically obtainable by the oral or parenteral route. However, local application of the D-lactic acid dimer onto or into tumors could be tumoricidal and useful as a debulking agent. Local application of chemotherapeutic drugs has been performed during neurosurgery where topical application of carmustine implants, Gliadel® Wafers, treat glioblastomas. (Perry et al 2007)
There are other potential uses of D-lactic acid dimer. These include local application to nerves for analgesia and local application to areas of high rates of glycolysis such as occur in Plasmodium aggregates. (Goldberg 2014, 2015, 2015)
We previously showed that oligomers of PDLA have cytotoxic properties when incubated with fresh leukemia cells compared to a control of Polymer L-lactic acid (PLLA). However, the cytotoxicity occurred at low pH (˜4), which obscured the findings. (Goldberg, Weinberg 2014, 2016)
This invention is an improvement over previous inventions. It definitively demonstrates that local application of D-lactic acid dimer to cultured cancer cells kills the cancer cells, and the killing is independent of the changes in pH when the dimer is applied. This invention demonstrates that D-lactic acid dimer could debulk the vast majority of tumors that depend upon glycolosis for production of ATP.
Table 1 is a summary of the figures.
TABLE 1Trypan blue viability studies of HeLa, retinoblastoma, and normal fibroblast cellsFIG.Cell typeDrug administeredTrypan blue staining for non-viable cells1HeLa10 mg D-lactic acid dimer100% cells non-viable2HeLa5 mg D-lactic acid dimer80% cells non-viable3HeLa5 mg PLLAless than 5% cells non-viable4HeLa5 mg L-lactic acid0% cells non-viable5HeLa2.5 mg L-lactic acid0% cells non-viable6HeLano treatment0% cells non-viable7Retinoblastoma25 mg D-lactic acid dimer50% cells non-viable8Retinoblastoma12.5 mg D-lactic acid dimer50% cells non-viable9Retinoblastoma6.25 mg D-lactic acid dimer30% cells non-viable10Retinoblastoma3.13 mg D-lactic acid dimer0% cells non-viable11Retinoblastoma1.5 mg D-lactic acid dimer0% cells non-viable12Retinoblastomano treatment0% cells non-viable13Fibroblast6 mg D-lactic acid dimer0% cells non-viable14Fibroblast6 mg L-lactic acid100% cells non-viable15Fibroblast3.13 mg D-lactic acid dimer0% cells non-viable16Fibroblast3.13 mg L-lactic acid40% cells non-viable